Background Pancreatic cancer is one of the most lethal malignancies and has an extremely poor diagnosis and prognosis. The development of resistance to gemcitabine is still a major challenge. The long noncoding RNA PVT1 was reported to be involved in carcinogenesis and chemoresistance; however, the mechanism by which PVT1 regulates the sensitivity of pancreatic cancer to gemcitabine remains poorly understood. Methods The viability of pancreatic cancer cells was assessed by MTT assay in vitro and xenograft tumor formation assay in vivo. The expression levels of PVT1 and miR-619-5p were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Western blotting analysis and qRT-PCR were performed to assess the protein and mRNA levels of Pygo2 and ATG14, respectively. Autophagy was explored via autophagic flux detection under confocal microscopy and autophagic vacuole investigation under transmission electron microscopy (TEM). The functional role and mechanism of PVT1 were further investigated by gain- and loss-of-function assays in vitro. Results In the present study, we demonstrated that PVT1 was up-regulated in gemcitabine-resistant pancreatic cancer cell lines. Gain- and loss-of-function assays revealed that PVT1 impaired sensitivity to gemcitabine in vitro and in vivo. We further found that PVT1 up-regulated the expression of both Pygo2 and ATG14 and thus regulated Wnt/β-catenin signaling and autophagic activity to overcome gemcitabine resistance through sponging miR-619-5p. Moreover, we discovered three TCF/LEF binding elements (TBEs) in the promoter region of PVT1, and activation of Wnt/β-catenin signaling mediated by the up-regulation of Pygo2 increased PVT1 expression by direct binding to the TBE region. Furthermore, PVT1 was discovered to interact with ATG14, thus promoting assembly of the autophagy specific complex I (PtdIns3K-C1) and ATG14-dependent class III PtdIns3K activity. Conclusions These data indicate that PVT1 plays a critical role in the sensitivity of pancreatic cancer to gemcitabine and highlight its potential as a valuable target for pancreatic cancer therapy.

Highlights Neutralizing antibody evaluation helps to assess the risk of re-infection. Some COVID-19 patients may not develop neutralizing antibody after recovery. SARS-CoV-2 neutralizing antibody levels are correlated with COVID-19 disease severity.

Background The SARS-CoV-2 B.1.617.2 (Delta) variant has caused a new surge in the number of COVID-19 cases. The effectiveness of inactivated vaccines against this variant is not fully understood. Methods Using data from a recent large-scale outbreak of B.1.617.2 SARS-COV-2 infection in Jiangsu, China, we conducted a real-world study to explore the effect of inactivated vaccine immunization on the course of disease in patients infected with the Delta variant. Results Out of 476 patients with B.1.617.2 infection, 184 were unvaccinated, 105 were partially vaccinated, and 187 were fully vaccinated. Forty-two (8.8%) patients developed severe illness, of which 27 (14.7%), 13 (12.4%), and 2 (1.1%) were unvaccinated, partially vaccinated, and fully vaccinated, respectively ( P <0.001). All 15 (3.2%) patients who required mechanical ventilation were unvaccinated. After adjusting for age, sex, and comorbidities, fully vaccinated patients had an 88% reduced risk of progressing to severe illness (OR adjusted : 0.12, 95% CI: 0.02-0.45). However, this protective effect was not observed in partially vaccinated patients (OR adjusted : 1.11, 95% CI: 0.51-2.36). Full immunization offered 100% protection from severe illness among women. The effect of the vaccine was potentially affected by underlying medical conditions (OR adjusted : 0.26, 95% CI: 0.03-1.23). Conclusion Full vaccination with inactivated vaccines is highly effective at preventing severe illness in Delta variant-infected patients. However, partial vaccination does not offer clinically meaningful protection against severe disease.

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